5,9α-Imino- or 6,9α-iminomethylene-9-deoxy-PGF1 compounds

ABSTRACT

This invention relates to certain structural and pharmacological analogs of prostacyclin (PGI 2 ) wherein a nitrogen is substituted for the 6,9α-epoxy-oxygen of prostacyclin. These novel nitrogen-containing prostacyclin-type compounds are useful for the pharmacological purposes for which prostacyclin is used, e.g., as antithrombotic agents, antihypertensive agents, antiasthma agents, nasal decongestants, or regulators of tertility and procreation.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of Ser. No. 807,514, filed June 17, 1977, now U.S. Pat. No. 4,097,489, issued June 27, 1978.

The present invention relates to prostacyclin analogs, the essential material constituting a disclosure thereof is incorporated here by reference from Ser. No. 807,514, filed June 17, 1977 now U.S. Pat. No. 4,097,489, issued June 27, 1978. 

I claim:
 1. A prostacyclin analog of the formula ##STR1## wherein R₂ is hydrogen or alkyl of one to 4 carbon atoms, inclusive, or alkylcarbonyl of one to 4 carbon atoms, inclusive;Wherein one of p and q is the integer one and the other is the integer zero; Wherein Z₁ is(1) --(CH₂)_(g) --CH₂ --CH₂ --, (2) --(ch₂)_(g) --CH₂ --CF₂ --, or (3) trans--(CH₂)_(g) --CH═CH--,wherein g is the integer zero, one, or 2; Wherein R₈ is hydrogen, hydroxy, or hydroxymethyl; Wherein Y₁ is(1) trans--CH═CH-- (2) cis--CH═CH--, (3) --ch₂ ch₂ --, (4) trans--CH═C(Hal)--, or (5) --C.tbd.C--wherein Hal is chloro or bromo; Wherein M₁ is ##STR2## wherein R₅ is hydrogen or alkyl with one to 4 carbon atoms, inclusive, Wherein L₁ is ##STR3## A MIXTURE OF ##STR4## and ##STR5## wherein R₃ and R₄ are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R₃ and R₄ is fluoro only when the other is hydrogen or fluoro; wherein X₁ is(1) --COOR₁ wherein R₁ is hydrogen; alkyl of one to 12 carbon atoms, inclusive; cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive; phenyl; phenyl substituted with one, two, or three chloro or alkyl of one to 3 carbon atoms; phenyl substituted in the para position by ##STR6## wherein R₂₆ is methyl, phenyl, acetamidophenyl, benzamidophenyl, or --NH₂ ; R₂₆ is methyl, phenyl, --NH₂, or methoxy; and R₂₇ is hydrogen or acetamido, inclusive; or a pharmacologically acceptable cation; (2) --CH₂ OH; or (3) --COL₄, wherein L₄ is (a) amino of the formula --NR₂ LR₂₂, wherein R₂₁ and R₂₂ are(i) hydrogen; (ii) alkyl of one to 12 carbon atoms, inclusive; (iii) cycloalkyl of 3 to 10 carbon atoms, inclusive; (iv) aralkyl of 7 to 12 carbon atoms, inclusive; (v) phenyl; (vi) phenyl substitutted with one, 2, or 3 chloro, alkyl of one to 3 carbon atoms, inclusive, hydroxy, inclusive, carboxy, alkoxycarbonyl of one to 4 carbon atoms, inclusive, or nitro; (vii) carboxyalkyl of one to four carbon atoms, inclusive; (viii) carbamoylalkyl of one to four carbon atoms, inclusive; (ix) cyanoalkyl of one to four carbon atoms, inclusive; (x) acetylalkyl of one to four carbon atoms, inclusive; (xi) benzoylalkyl of one to four carbon atoms, inclusive; (xii) benzoylalkyl substituted by one, 2, or 3 chloro, alkyl of one to 3 carbon atoms inclusive; hydroxy, alkoxy of one to 3 carbon atoms, inclusive; carboxy, alkoxycarbonyl of one to 4 carbon atoms, inclusive, or nitro; (xiii) hydroxyalkyl of one to 4 carbon atoms, inclusive; (xiv) dihydroxyalkyl of one to 4 carbon atoms; and (xv) trihydroxyalkyl of one to 4 carbon atoms; with the further proviso that not more than one of R₂₁ and R₂₂ is other than hydrogen or alkyl; (b) carbonylamino of the formula --NR₂₃ COR₂₁, wherein R₂₃ is hydrogen or alkyl of one to 4 carbon atoms and R₂₁ is as defined above; (c) sulphonylamino of the formula --NR₂₃ SO₂ R₂₁, wherein R₂₁ and R₂₂ are as defined above; or (d) hydrazino of the formula --NR₂₃ R₂₄, wherein R₂₄ is amino of the formula --NR₂ LR₂₂, as defined above; wherein R₇ is(1) --(CH₂)_(m) --CH₃, ##STR7## wherein m is the integer one to 5, inclusive, h is the integer zero to 3, inclusive; s is the integer zero, one, 2, or 3, and T is chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, or with the proviso that not more than two T's are other than alkyl; and the pharmacologically acceptable acid addition salts thereof when R₂ is not alkylcarbonyl and R₁ is not a pharmacologically acceptable cation.
 2. A prostacyclin analog according to claim 1, wherein R₈ is hydroxymethyl.
 3. 9,11-Dideoxy-11α-hydroxymethyl-9α,6-iminomethylene-PGF₁, a prostacyclin analog according to claim
 2. 4. A prostacyclin analog according to claim 1, wherein R₈ is hydrogen.
 5. 9,11-Dideoxy-9α,6-iminomethylene-PGF₁, a prostacyclin analog according to claim
 4. 6. A prostacyclin analog according to claim 1, wherein R₈ is hydroxy.
 7. A prostacyclin analog according to claim 6, wherein p is one.
 8. 9-Deoxy-5,9α-imino-PGF₁, a prostacyclin analog according to claim
 7. 9. A prostacyclin analog according to claim 6, wherein q is one.
 10. A prostacyclin analog according to claim 6, wherein R₂ is not hydrogen.
 11. (6R)-N-methyl-6,9α-iminomethylene-PGF₁, a prostacyclin analog according to claim
 10. 12. (6R)-N-acetyl-6,9α-iminomethylene-PGF₁, a prostacyclin analog according to claim
 10. 13. (6S)-N-methyl-6,9α-iminomethylene-PGF₁, a prostacyclin analog according to claim
 10. 14. (6S)-N-acetyl-6,9α-iminomethylene-PGF₁, a prostacyclin analog according to claim
 10. 15. A prostacyclin analog according to claim 6, wherein R₂ is hydrogen.
 16. A prostacyclin analog according to claim 15, wherein Y₁ is cis--CH═CH--.
 17. 9-Deoxy-9α,6-iminomethylene-cis-13-PGF₁, a prostacyclin analog according to claim
 16. 18. A prostacyclin analog according to claim 15, wherein Y₁ is --C.tbd.C--.
 19. 9-Deoxy-9α,6-iminomethylene-13,14-didehydro-PGF₁, a prostacyclin analog according to claim
 18. 20. A prostacyclin analog according to claim 15, wherein Y₁ is trans--CH═C(Hal)--.
 21. 9-Deoxy-9α,6-iminomethylene-14-chloro-PGF₁, a prostacyclin analog according to claim
 20. 22. A prostacyclin analog according to claim 15, wherein Y₁ is --CH₂ CH₂ --.
 23. 9-Deoxy-9α,6-iminomethylene-13,14-dihydro-PGF₁, a prostacyclin analog according to claim
 22. 24. A prostacyclin analog according to claim 15, wherein Y₁ is trans--CH═CH--.
 25. A prostacyclin analog according to claim 24, wherein Z₁ is --(CH₂)_(g) --CH₂ --CF₂.
 26. 2,2-Difluoro-9-deoxy-9α,6-iminomethylene-15-methyl-PGF₁, a prostacyclin analog according to claim
 25. 27. A prostacyclin analog according to claim 24, wherein Z₁ is trans--(CH₂)_(g) --CH═CH--.
 28. Trans-2,3-didehydro-9-deoxy-9α,6-iminomethylene-PGF₁, a prostacyclin analog according to claim
 27. 29. A prostacyclin analog according to claim 24, wherein Z₁ is --(CH₂)_(g) --CH₂ --CH₂ --.
 30. A prostacyclin analog according to claim 29, wherein g is zero.
 31. A prostacyclin analog according to claim 30, wherein R₇ is ##STR8##
 32. 9-Deoxy-9α,6-iminomethylene-17-phenyl-18,19,20-trinor-PGF₁, a prostacyclin analog according to claim
 31. 33. A prostacyclin analog according to claim 30, wherein R₇ is ##STR9##
 34. 9-Deoxy-9α,6-iminomethylene-16-phenoxy-17,18,19,20-tetranor-PGF.sub.1, a prostacyclin analog according to claim
 33. 35. A prostacyclin analog according to claim 30, wherein R₇ is --(CH₂)_(m) --CH₃.
 36. A prostacyclin analog according to claim 35, wherein m is
 3. 37. A prostacyclin analog according to claim 36, wherein X₁ is --COL₄.
 38. 9-Deoxy-9α,6-iminomethylene-PGF₁, amide, a prostacyclin analog according to claim
 37. 39. A prostacyclin analog according to claim 37, wherein X₁ is CH₂ OH.
 40. 2-Decarboxy-2-hydroxymethyl-9-deoxy-9α,6-iminomethylene-PGF₁, a prostacyclin analog according to claim
 39. 41. A prostacyclin analog according to claim 36, wherein X₁ is --COOR₁.
 42. A prostacyclin analog according to claim 41, wherein R₅ is methyl.
 43. 9-Deoxy-9α,6-iminomethylene-PGF₁, a prostacyclin analog according to claim
 42. 44. A prostacyclin analog according to claim 41, wherein R₅ is hydrogen.
 45. A prostacyclin analog according to claim 44, wherein at least one of R₃ and R₄ is fluoro.
 46. 9-Deoxy-9α,6-iminomethylene-16,16-difluoro-PGF₁, a prostacyclin analog according to claim
 45. 47. A prostacyclin analog according to claim 44, wherein at least one of R₃ or R₄ is methyl.
 48. 9-Deoxy-9α,6-iminomethylene-16,16-dimethyl-PGF₁, a prostacyclin analog according to claim
 47. 49. A prostacyclin analog according to claim 48, wherein R₃ and R₄ are both hydrogen.
 50. 9-Deoxy-9α,6-iminomethylene-PGF₁, methyl ester, a prostacyclin analog according to claim
 49. 51. 9-Deoxy-9α,6-iminomethylene-PGF₁, tris(hydroxymethyl)amino methane salt, a prostacyclin analog according to claim
 49. 52. 9-Deoxy-9α,6-iminomethylene-PGF₁, hydrochloride, a prostacyclin analog according to claim
 49. 53. 9-Deoxy-9α,6-iminomethylene-PGF₁, a prostacyclin analog according to claim
 49. 